Epidemiological studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs), notably, ibuprofen and naproxen and other non-selective cyclooxygenase (COX) inhibitors) are associated with lower risk for Alzheimer Disease (AD). That this association is causal is supported by work from our group and others, showing that ibuprofen reduced cognitive deficits and evidence of plaque pathogenesis in AD animal models. Even short term naproxen or ibuprofen corrected LTP and cognitive deficits, prior to detectable reduction in A. Naproxen went into an AD prevention trial called ADAPT, which is now emerging as reducing AD risk 58% (p=0.01, ICAD July 08, J. Breitner). The mechanisms remain unclear because unlike ibuprofen, naproxen does not lower A42 production via -secretase. Our data show that naproxen can also suppress the A- oligomer-induced neurodegeneration postulated to cause cognitive deficits. A oligomers are small assemblies of A peptide implicated in AD pathogenesis, which are now shown to bind selectively to excitatory synapses at postsynaptic sites and cause dendritic spine and synapse loss, similar to observed early in hippocampal and temporal regions in AD. Our lab and others have implicated oligomer-induced dysregulation of rac signaling pathways known to influence cognitive function; more specifically we focused on rac>PAK>LIMK1>cofilin control of actin assembly and disassembly in dendritic spines as a mechanism of synapse loss (Zhao et al., 2006). We then found that fyn kinase was upstream of this pathway (Ma et al., 2008) consistent with fyn knockout suppressing A synaptotoxicity (Chin et al., 2005; Chin et al., 2004) and that defects in this pathway could be corrected by COX inhibitors resulting in reduced synaptotoxicity in vitro and in vivo. Fyn binds tau and accumulates in tangle bearing neurons in AD, suggesting the need to test NSAIDs in models with tau pathology. Since ADAPT trial was halted over safety concerns, we continue to investigate ibuprofen, which has strong rationale and a better safety profile than naproxen at efficacious dosages. Consistent with our data showing different benefits from NSAIDs and antioxidants, epidemiology supports combined NSAIDs and antioxidants (Fotuhi et al., 2008). Objectives. Aim 1) To use primary neuron cultures to determine: (a) relative roles of COX-1 and COX-2 in NSAID protection from A oligomer- induced synapse loss, believed to cause cognitive deficits in AD; (b) how COX influences A-induced loss of synapses and (c) whether NSAIDs, which fail to reduce oxidative damage, synergize with a natural antioxidant, -lipoate, to protect synapses from A. Aim 2) will evaluate the role of ibuprofen, naproxen or the antioxidant -lipoate in triple transgenic mice with tau pathology with early and late intervention and whether they protect from synapse loss, tau pathology, neurodegeneration and cognitive deficits. Aim 3) will evaluate whether short term treatment with NSAIDs, followed by withdrawal, will lead to persistence of treatment effects, and whether NSAIDs synergize with -lipoate, an antioxidant reported to slow AD progression.